The transdermal route to drug delivery has the advantages associated with rate-controlled drug-delivery systems (e.g., greater safety, effectiveness, and convenience). In addition, unlike other rate-controlled systems, transdermal drug delivery avoids hepatic "first pass" effects and gastrointestinal incompatibility, and offers the potential for localized drug delivery. The primary factor responsible for the limited use of transdermal drug delivery is the low transdermal permeability of most drugs. Although a number of agents have been identified that increase the transdermal permeation of specific drugs, the utility of such agents, termed penetration enhancers, is often limited by rapid clearance from the application site through evaporation or transdermal permeation. In the proposed program, we will determine whether the utility of penetration enhancers can be increased by sustaining their delivery to the skin surface. Our principal objective will be to demonstrate that microencapsulated enhancers have the ability to maintain effective enhancement properties over extended periods of time. By sustaining the delivery of enhancers, we expect to increase the amount of drug that can be delivered in a single topical application and to extend the delivery lifetimes of current transdermal delivery systems.